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Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells
Guinevere Q. Lee, … , Xu G. Yu, Mathias Lichterfeld
Guinevere Q. Lee, … , Xu G. Yu, Mathias Lichterfeld
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2689-2696. https://doi.org/10.1172/JCI93289.
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Research Article AIDS/HIV

Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells

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Abstract

HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.

Authors

Guinevere Q. Lee, Nina Orlova-Fink, Kevin Einkauf, Fatema Z. Chowdhury, Xiaoming Sun, Sean Harrington, Hsiao-Hsuan Kuo, Stephane Hua, Hsiao-Rong Chen, Zhengyu Ouyang, Kavidha Reddy, Krista Dong, Thumbi Ndung’u, Bruce D. Walker, Eric S. Rosenberg, Xu G. Yu, Mathias Lichterfeld

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Figure 1

HIV-1 DNA levels in highly purified populations of functionally polarized memory CD4+ T cells.

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HIV-1 DNA levels in highly purified populations of functionally polarize...
(A) Relative proportions of memory CD4+ T cells with the indicated functional polarization in HIV-1–infected individuals with acute infection, chronic untreated progressive infection, and cART-treated infection; in HIV-1 controllers; and in uninfected individuals (HIV neg). Significance was tested using a Kruskal-Wallis test with Dunn’s multiple comparisons test. (B) SPICE diagrams reflecting proportions of polarized memory CD4+ T cells with indicated cytokine secretion profiles in the different study cohorts. (C) Per-cell levels of HIV-1 gag DNA in sorted memory CD4+ T cells from cART-treated individuals with the indicated functional polarization. Empty symbols reflect data points at calculated limits of detection. Significance was tested using a Friedman test with Dunn’s multiple comparisons test. (A and C) *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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